PROJECT SUMMARY Three of top five causes of death in humans globally are lung-related; chronic obstructive pulmonary disease (COPD), lower respiratory infections and lung cancers collectively account for over eight million deaths annually. Currently, in preclinical setting, static cell cultures and animal models are the most widely used systems for mechanistic and translational studies. However, critical limitations of these systems often hinder the translation of findings to humans. As such, there is a bottleneck on clinical translation, drug development, biomarker discovery and mechanistic studies in pulmonary field, particularly COPD, due to lack of reliable, and human- and disease-relevant preclinical models. Here, we propose to apply tissue microengineering principles from emerging ?Organ-on-Chip? technology, to develop and commercialize ?Next-Generation Bioartificial Human Lung? as an improved experimental research tool to evaluate human lung airway pathophysiology in vitro. This highly innovative microfluidic cell culture device will contain micrometer-sized hollow channels inhabited by human- derived (healthy and diseased) living cells that will recreate multicellular architecture, tissue-tissue interfaces, and physicochemical microenvironment of the human lung airway, and will enable reproduction of in vivo-observed vascular perfusion that is crucial for providing nutrients, oxygen and growth factors to this organomimetic culture system. Our business hypothesis is that for laboratory investigators who conduct pulmonary research, the Bioartificial Human Lung provides an experimental research tool that enables them to considerably accelerate clinical translation of their basic science, better than animal models, static 2D culture systems and even currently available microfluidic systems, by enhanced reproduction of complex human organ pathophysiology in vitro. To test this hypothesis, in Phase I of the project, we will pursue these specific aims: (1) to demonstrate feasible fabrication and assembly of the Bioartificial Human Lung, and (2) to provide proof-of- principle data on establishing a living multi-cellular co-culture containing extracellular matrix and matrix-embedded stromal cells in our proposed microdevice. At the completion of Phase I, it is our expectation that we will have the capability to consistently and reproducibly manufacture the proposed Bioartificial Human Lung and culture primary cells isolated from the human airway in this device and maintain them viable and functional for weeks. This will allow for transition to Phase II to apply the new chip technology to reproduce various lung pathologies, and refine mass scale production capabilities through reproducibility and cost minimization. Ultimately, a commercial product, which enables enhanced clinical translation in the pulmonary field and facilitates faster-paced drug development and biomarker discovery, will be available as end-user off-the-shelf product.